Amino acids are carboxylic acids with an amino group at the .alpha. or C-2 position. They have the general formula RCH(NH.sub.2)CO.sub.2 H. Except for glycine, wherein R is H, all have a center of asymmetry at the .alpha. position, and thus can exist in either of two enantiomeric forms (the D and the L configurations). The naturally occurring amino acids are in the L configuration. That is, they have the following projection formula. ##STR4##
Optically active a-methylated amino acid analogs (compounds of the above formula wherein H is replaced by methyl and R is a residue corresponding to a natural or unnatural amino acid), particularly those having the L enantiomeric configuration corresponding to the naturally occurring amino acids, are known to be useful for a variety of purposes. Some .alpha.-methylated amino acids, such as for example methyldopa (L-.alpha.-methyl-3,4-dihydroxyphenylalanine), are useful as therapeutic agents. Others can be used as intermediates for the production of other useful substances. For example, as described in International Application No. PCT/US98/04254, .alpha.-methylated amino acid analogs can be used as intermediates to make certain hydantoins that are useful for treating or preventing inflammatory and immune cell-mediated diseases.
The prior art provides two general approaches for the synthesis of optically active .alpha.-methylated amino acids (and amino acid esters). The first general approach is to prepare a racemic product and then resolve the enantiomers. The second general approach, sometimes termed the enantioretentive approach, starts with an optically active .alpha.-amino acid and replaces the .alpha.-hydrogen while retaining, in the final product, the initial enantiomeric configuration.
A known method for the enantioretentive .alpha.-alkylation of amino acids takes advantage of a technique called the "self-regeneration of stereocenters", first introduced by Seebach et al. (Angew. Chem. Int. Ed. Engl. 1996, 35, 2708). This method is depicted in Scheme 1, below, for the amino acid alanine. ##STR5##
In accordance with this technique, an optically pure amino acid containing one stereogenic center is reacted with an aldehyde (or aldehyde equivalent) to form an oxazolidinone having a second stereogenic center. Two isomers of the acetal are possible, but the formation of the cis isomer is usually preferred. (As the optical purity of the final product depends on the diastereomeric purity of the acetal, the unwanted trans isomer is usually removed, as by recrystallization or chromatography.) Reaction of the acetal with a base yields an enolate (such as, for example, the Li-enolate) in which the original stereogenic center has been destroyed (turned into a trigonal center), but in which chirality has been retained due to the second stereogenic center previously introduced. Reaction of the enolate with an electrophile results in the formation of an alkylated oxazolidinone. Alkylation, which takes place at the trigonal center, proceeds diastereoselectively, due to the influence of the second stereogenic center. Subsequent hydrolysis of the alkylated oxazolidinone yields an a-alkylated amino acid in which the absolute configuration of the original chiral center has been retained.
It will be noted that this synthetic technique essentially comprises three steps. The first step creates, as a key intermediate, an oxazolidinone template of the general formula ##STR6## wherein R is part of an additional stereogenic center contributed by the aldehyde or aldehyde equivalent and R.sub.1 CO-- is an appropriate protecting group. The second step involves alkylation of the oxazolidinone template with a base and an alkyl halide. The third step involves transformation of the N-protected and alkylated oxazolidinone into the desired .alpha.-methylated amino acid.
With respect to the first step, it should be noted that the literature provides two related approaches to the production of the oxazolidinone template. The two methods, depicted in Schemes 2 and 3, below, differ only in the order of introduction of the reagents. ##STR7##
In the first method (Scheme 2), originally described by Seebach (Helv. Chim. Acta 1985, 68,1243) the amino acid sodium salt 1 is treated first with an aldehyde to yield Schiff base 2. Acylation of this species presumably yields an intermediate acyliminium ion, 3, which then undergoes attack by the internal nucleophile, the carboxylate anion, thus forming the cyclic oxazolidinone template 4.
In the second method (Scheme 3), first described by Karady (Tetrahedron Lett. 1984, 25, 4337; U.S. Pat. No. 4,508,921), the same amino acid salt is first acylated, then activated by condensation with an aldehyde or equivalent, presumably to the same acyliminium ion 3, which then cyclizes as above.
As noted above, the utility of these procedures strongly depends on the ability to reproducibly and predictably generate a well-defined stereochemical relationship (cis or trans) between the .alpha.-methyl group and the new stereogenic center in 4. Both methods are unsatisfactory in this respect.
For example, by using the method of Scheme 2, Seebach et al. (Helv. Chim. Acta 1985, 68, 1243) reports a high yield of 4 (92%) but only a modest selectivity (2.5:1 to 5: 1) in favor of the cis isomer, depending for unclear reasons on the specific experimental protocol employed (R=tBu; R.sup.1 =Ph). By using the same method, Fadel et al. (Tetrahedron Lett. 1987, 28, 2243) also find variable ratios of cis/trans always favoring the cis isomer (from 3:1 to 7.5: 1) in high chemical yield (94%, R=R.sup.1 =Ph). On the other hand, Mutter et al. (Helv. Chim. Acta 1991, 74, 800) use this method to obtain a mixture of isomers favoring the trans isomer (2.5:1; R=Ph, R.sup.1 =PhCH.sub.2 O). Lavergne et al. (J. Organomet. Chem. 1991, 401, C10) obtain, by the same method, a good yield (81%) of a 3:1 cis:trans mixture. Mutter et al. (Tetrahedron Lett. 1988, 44, 4793) separately report on using the same method to obtain a low yield (50%) of the trans isomer exclusively (R=R.sup.1 =Ph). In direct contrast, Alonso et al. (Tetrahedron Asymmetry 1995, 6, 353) obtain only the cis isomer in good yield (92%), again using the same protocol (R=ferrocenyl, R.sup.1 =tBu). Accordingly, it is evident that Method A lacks in predictability and reproducibility, and can lead, under apparently similar conditions but slight structural changes in R and R.sub.1, to cis/trans mixtures in any ratio ranging from only trans to only cis. The reasons for this inconsistent behavior have not been investigated.
Likewise, the method of Scheme 3, (Tetrahedron Lett. 1984, 25, 4337), employed less often, is also unsatisfactory because it proceeds in poor yield and gives a modest cis:trans ratio of 4:1 (R=2,4--Cl.sub.2 -C.sub.6 H.sub.3 ; R.sup.1 =BnO).